How do T cells, the beat cops of the immune system, detect signs of disease without the benefit of eyes? Like most cells, they explore their surroundings through direct physical contact, but how T cells feel out intruders rapidly and reliably enough to nip infections and other threats in the bud has remained a mystery to researchers.
In a new study, published online May 11, 2017 in Science, UC San Francisco researchers began to address this question by using cutting-edge techniques to capture videos of the surface of living T cells in more detail than ever before. Researchers had previously observed tentacle-like protrusions called microvilli covering the surface of T cells, but the new research revealed that these tentacles are in constant motion: they crawl across the cell surface, each independently searching for signs of danger or infection in a fractal-like pattern that allows T cells to spend the minimum time necessary feeling for a potential threat before moving on.
"Previous techniques had allowed us to take snapshots of the surface of T cells, but that's like trying to understand a basketball game by studying a black-and-white photo," said Matthew Krummel, PhD, associate professor of pathology at UCSF and senior author of the new study. "Now we can watch these amazing little fingers of membrane move around in real-time - and it turns out they're incredibly efficient."
Among other potential benefits, Krummel says, understanding how T cells efficiently sample their environment to search for invasive pathogens opens up new questions about what countermeasures infectious organisms or even cancer cells may have evolved as a way of avoiding detection, and could suggest new ways for researchers to help T cells see through such a ruse.
Efficient search by T cells is key to an effective immune response
As they make their rounds through the body, T cells make contact with a network of informants -- other immune cells that scour the body for potential signs of danger and display the protein fragments they find (called "antigens") on their surface for inspection by the T cells. If a T cell meets one of these so-called antigen-presenting cells and recognizes a protein fragment it carries as evidence of danger, the T cell sounds the alarm and triggers a more global immune response to fight off the invaders.
Scientists estimate that you have only about 100 T cells in your body at any given moment that can recognize and responding to a specific antigen, such a protein from this year's flu virus, and these few cells each take days to patrol your entire body, Krummel said. "This means the immune system really needs to get ahead of whatever is attacking the body at the very first evidence that there's an intruder on board. If one T cell misses the signs of a virus, the next time a cell that can recognize the threat might come through that tissue, the virus has had hours to make tens of thousands of copies of itself."
New imaging techniques reveal how immune cells "talk" using touch
In the Science study, Krummel's team was able to study how T cells efficiently interrogate antigen-presenting cells in real time, thanks to a high-resolution cellular imaging technique called lattice light-sheet microscopy, which the team set up at UCSF in collaboration with its inventor, 2014 Nobel prize winner and study co-author Eric Betzig, PhD, of the Howard Hughes Medical Institute's Janelia Research Campus in Virginia.
Using this technology, the team studied mouse T cells exploring simulated patches of antigen-presenting cell membrane in laboratory dishes, and found that the T cell microvilli move independently of one another in a fractal-like geometry, such as is often seen in nature as a way of optimizing efficient use of space, such as by plant roots or foraging animals.
The researchers calculated that, thanks to this efficient search pattern, in an average minute-long encounter win an antigen-presenting cell, T cell microvilli can thoroughly explore 98 percent of the contact surface between the two cells -- called an "immunological synapse" after the neuronal synapses of the nervous system. This suggests that T cells are tuned to spend the minimum time necessary to get a clear read on the information available at each antigen-presenting cell before moving on, the authors say.
To study the details of threat detection by microvilli, the authors devised a new approach that allowed them to simultaneously track microvilli as well as the T cell receptor (TCR) proteins T cells use to detect their target antigens. To do this, the team covered simulated patches of antigen-presenting cell membrane with tiny fluorescent particles called quantum dots, which questing T cell microvilli had to push out of the way to reach the membrane surface. This technique, dubbed synaptic contact mapping, allowed the researchers to visualize the microvilli as holes of negative space in the quantum dot fluorescence, while at the same time visualizing TCRs with a different-colored fluorescent marker.
They found that normally, individual microvilli poke and prod at the antigen-presenting cell membrane for an average of about four seconds at a time. But when the microvilli found the antigen they were searching for, they stayed in contact with the antigen-presenting cell membrane for 20 seconds or more and accumulated large rafts of TCRs, suggesting that they were likely signaling the T cell to trigger its immune response.
"These videos give me a much more visceral understanding of what's happening when T cells and antigen-presenting cells come into contact," Krummel said. "T cells have these anemone-like sensory organs, and when they want to get information from another cell, their only chance appears to be during this short period of intimate contact. If they don't detect a strong signal during that contact, they move on."
Real-time imaging technology opens new opportunities to study immunity and disease
Krummel's team also briefly studied the surfaces of other types of immune cells, such as dendritic cells and B cells, which play different roles in pathogen detection and immune response. They found that each cell type appears to use distinct patterns of surface protrusions -- such as tentacles, waves, or curtain-like ripples -- to probe and communicate with their environments, though more research is needed to understand these diverse patterns and how they interact with one another. (See video.)
"Understanding how the immune system reliably detects and responds to the huge range of potential threats it has to deal with is one of the key questions we still face as immunologists," Krummel said. "Of course, the immune system also makes mistakes -- like when it attacks the body's own cells in autoimmune disease or fails to recognize cancerous cells as a threat. Understanding the mechanics and constraints of how the immune system recognizes threats in the first place could potentially help us correct those errors."
En Cai, PhD, Kyle Marchuk, PhD, Peter Beemiller, PhD, and Casey Beppler, BS, of UCSF, were co-first authors of the new study. Other authors were Matthew G. Rubashkin, PhD, Valerie M. Weaver, PhD, and Audrey Gérard, PhD, of UCSF; Tsung-Li Liu, PhD, and Bi-Chang Chen, PhD, of Janelia; and Frederic Bartumeus, PhD, of the Center for Advanced Studies of Blanes in Girona, Spain and Institut Català de Recerca i Estudis Avançats (ICREA) in Barcelona.
Funding for this research was provided by the National Institutes of Health (AI052116), National Cancer Institute (U01CA202241), a US Department of Defense National Defense Science and Engineering Graduate Fellowship, and a National Science Foundation Graduate Research Fellowship (1650113). Betzig is an inventor on patent application US 20130286181 A1, submitted by Howard Hughes Medical Institute (HHMI), which covers LLS imaging. The authors declare no competing financial interests.
About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland - and other partner and affiliated hospitals and healthcare providers throughout the Bay Area. Please visit http://www. .

Thin air can reverse brain damage due to mitochondrial defects in mice.
After a month of breathing air that contains about half the usual amount of oxygen, telltale lesions in the brains of these mice had disappeared, Howard Hughes Medical Institute (HHMI) Investigator Vamsi Mootha and colleagues report online May 8 in the Proceedings of the National Academy of Sciences.
"We found, much to our surprise and delight, that we could actually reverse advanced disease," Mootha said. "I don't think anybody thought that these types of neurological diseases could be reversible."
It's a remarkable turnaround -- though the result was seen in mice, not humans. More research is needed before a similar approach could be used to treat people, cautions Mootha, a mitochondrial biologist at Massachusetts General Hospital in Boston. Still, the findings hint at the promise of low oxygen therapy to prevent, or even reverse, mitochondrial disorders in people.
One such disorder is Leigh syndrome, a rare disease that often appears in the first few years of life. The disorder is marked by progressive brain lesions, a loss of motor skills, developmental delays and a failure to grow. Most forms of the disease have no proven treatments.
Yet Mootha and his team had what seems like a counterintuitive idea. In 2016, the researchers reported that hypoxia, or oxygen deficiency, actually improves the health of mice genetically engineered to have dysfunctional mitochondria, tiny power-producing organelles. Those results, published in Science, were tantalizing, and also raised a number of questions, such as how long these treated mice actually live, and whether hypoxia treatment needs to be continuous.
The new findings answer some of these questions. "At a high level, this is exploring the remarkable potential and also the limitations of hypoxia," Mootha said.
The mice in the study were genetically engineered to lack a gene called Ndufs4, which encodes a protein essential for a part of mitochondria called complex I. That same gene is mutated in some people with Leigh syndrome.
When these mice were housed in chambers that contained normal air containing 21 percent oxygen, the equivalent of what a person would breathe at sea level, they developed brain lesions and had a median survival length of 58 days. But when these mice were kept in chambers that contained 11 percent oxygen, their median survival time stretched to 270 days, Mootha and colleagues found. What's more, MRI images revealed these mice had no signs of abnormally bright brain tissue, lesions that often signal degeneration.
Eleven percent oxygen is close to what a person would encounter at high altitudes such as the base camp at Mount Everest. "Is it super comfortable? Certainly not," Mootha said, but a healthy person would be able to tolerate it.
Based on his team's earlier work, Mootha wasn't surprised that the mice treated with hypoxia lived longer. But a different result was unexpected: A switch to hypoxic conditions seemed to actually reverse existing brain damage. After a month of breathing low oxygen air, lesions in the mices' brains disappeared, MRI images revealed.
While the results in the mice are "profound and striking," Mootha emphasized that the research is still at an early stage. Much more work needs to be done before hypoxia can be used to treat people with mitochondria disorders. "We are not ready yet to go into the clinic," he said.
Other results help illustrate remaining hurdles to developing a hypoxia therapy. Mootha and his team had hoped to find benefits for more moderate low-oxygen conditions, such as intermittent periods of hypoxia or slightly higher levels of oxygen. But so far, the results suggest that only continuous 11 percent oxygen does the trick. "The disappointing part was that we didn't come up with a more practical regimen, at least in this paper," Mootha said.
Still, he and his team plan to keep looking for other ways to get the hypoxia benefits without the intense hypoxia conditions, perhaps with a small molecule. The researchers also plan to study how exactly the hypoxia response works -- how low-oxygen conditions kindle molecular efforts to protect and repair the brain.
The results have implications that stretch beyond mitochondrial diseases. Neurodegenerative disorders that have been associated with aging, and even normal aging, have been linked to a diminished mitochondrial power. "As all of us age, our mitochondrial activity declines," Mootha said. Hypoxia, or a drug that mimics a key aspect of it, might one day be able to rejuvenate flagging mitochondria, and perhaps the aging body, too.

Forty-one scientists from 16 countries have been chosen as International Research Scholars, exceptional early-career scientists poised to advance biomedical research across the globe.
The Howard Hughes Medical Institute (HHMI) has teamed up with the Bill & Melinda Gates Foundation, the Wellcome Trust, and the Calouste Gulbenkian Foundation to develop scientific talent around the world, and will award a total of nearly $26.7 million to this group of scholars. Each researcher will receive a total of $650,000 over five years. The award is a big boon for scientists early in their careers, and offers the freedom to pursue new research directions and creative projects that could develop into top-notch scientific programs.
"This is an outstanding group of scientists who will push biomedical research forward worldwide, and we are thrilled to support them alongside our philanthropic partners," said David Clapham, HHMI's Vice President and Chief Scientific Officer.
The scientists selected as International Research Scholars represent a diverse array of scientific disciplines and geographic locations. Scholars hail from research organizations and institutions from across the world, from Tanzania to Cambodia to Chile to Austria. Their research covers a broad variety of biological and medical research areas too, including neuroscience, genetics, biophysics, computational biology, and parasitology.
"We are excited to join with our partners in supporting these superb scientists. We look to them to bring transformative innovation to priority global health problems," said Chris Karp, Director of Global Health Discovery & Translational Sciences at the Bill & Melinda Gates Foundation.
These researchers' goals are innovative, wide-ranging, and forward-thinking. They seek to understand diverse topics, from how immune cells function to how pathogenic bacteria jump from the environment to humans, and are even investigating ways to watch genes switch on and off in living brains.
"We are delighted to be a partner in supporting this outstanding community of international researchers. Their expertise and thirst for knowledge will enhance our understanding of how life works and the causes and consequences of disease, said Anne-Marie Coriat, Head of Research Careers at Wellcome Trust.
A panel of distinguished scientists reviewed more than 1,400 applications, and evaluated both the impact of past work, including doctoral and postdoctoral achievements, and the promise of work to come. It's a researcher-focused approach that emphasizes the skills and talents of the individual, rather than solely the projects proposed.
"We are proud to partner with HHMI, the Bill and Melinda Gates Foundation and the Wellcome Trust to support this truly exceptional group of young biomedical scientists. Biomedical research is increasingly at the core of the work of our research institute, the Instituto Gulbenkian de Ciência," said Gulbenkian Institute Director Jonathan Howard.
HHMI, the Bill & Melinda Gates Foundation, the Wellcome Trust, and the Calouste Gulbenkian Foundation announced the 2017 International Research Scholar competition March 29, 2016. The competition was open to early-career scientists who held a full-time position at a research-oriented university, medical school, or nonprofit institution, and had been running their own labs for less than seven years. Candidates also had to work in an eligible country, and have received training in the United States or the United Kingdom for at least one year.
Ido Amit wants to reveal how immune cells work, and what role they play in health and disease. His lab develops new single cell genomic technologies to study these cells in unprecedented resolution. Figuring out immune cells' actions will help advance the next generation of immunotherapy to fight cancer and other disorders.
Melanie Blokesch studies Vibrio cholerae, a water-dwelling bacterium that wreaks havoc in the gut and causes the diarrheal disease cholera. Her team wants to map the molecular tools V. cholerae uses to jump from the environment to humans, which will help explain what triggers cholera outbreaks in endemic areas of the world.
Carlos Blondel investigates the emergence of human pathogens by studying their molecular weaponry. He has worked with foodborne pathogens that cause gastrointestinal disease, such as Salmonella and Vibrio parahaemolyticus. Blondel recently used CRISPR/Cas 9 genome editing technology to uncover key interactions between V. parahaemolyticus and human cells.
Yossi Buganim's goal is to bring therapeutic cells from the lab to the clinic. His team has invented and improved ways to reprogram adult cells into other cell types, including those able to generate nearly any kind of cell in the body. One day, such cells could be tapped for regenerative medicine replacing damaged tissues with those grown in the lab.
Tineke Cantaert seeks to understand how the immune system responds to infection by flaviviruses such as Dengue and Zika. Currently, no treatment exists for infection by either virus. Identifying biomarkers for protective immunity might help scientists speed up the development of therapies and vaccines.
Ling-Ling Chen is discovering new and unusual classes of RNA molecules called long noncoding RNAs. She's figuring out how these molecules form, what role they play in gene regulation, and how they may influence disease. She has found that some of these RNAs are conspicuously absent in people with the neurodevelopmental genetic disorder Prader-Willi syndrome.
Mark Dawson is searching for ways to wipe out malignant stem cells without harming normal stem cells. He studies cancers such as acute myeloid leukemia, which are difficult to eradicate using traditional chemotherapies. Understanding how normal and malignant stem cells differ from each other could let researchers devise more effective, targeted treatments.
Ana Domingos is investigating new molecular strategies to fight obesity. She has discovered a direct link between fat tissue and neurons of the sympathetic nervous system, which plays a role in burning fat. Stimulating these neurons could one day lead to a new treatment to cause fat loss.
Idan Efroni is unraveling the mystery of plants' impressive regenerative abilities. He uses tomatoes to study how plants generate new stem cells and meristems to replace damaged or missing roots. Insight into this process might reveal clues about tissue regeneration in other organisms, and help scientists boost plant production for agriculture.
Eran Elinav is fascinated by microbes that live around and in our body our microbiome. He has discovered important links between nutrition, gut microbes and the risk of developing common diseases, such as obesity and diabetes. Now, he wants to figure out how gut microbes impact human relapsing (or "yo-yo") obesity and its many complications.
Qiaomei Fu is exploring the genetic roots of humankind. Her work has helped untangle the early history of modern humans and Neanderthals, and reveal how early agriculture affected European farmers. She wants to illuminate the human prehistory of Asia by investigating the ancient genomes of both humans and pathogens.
Lena Ho is on the hunt for new peptides linked to human disease. She's looking for hidden gems among previously overlooked regions of our genome, and seeks to understand how the peptides work and how they can be used to combat common diseases of the cardiovascular and metabolic systems.
Kathryn Holt uses genomic tools to study infectious disease-causing microbes important in global health, including Salmonella typhi, which causes typhoid fever, and Shigella sonnei, a bacterium responsible for dysentery. She wants to understand what makes pathogens emerge, and why some become resistant to antimicrobial drugs.
In developing animal embryos, stem cell growth is tightly regulated so that the right kinds of cells emerge at the proper place and time. Catarina Homem is investigating how metabolism and nutrition influence this process, and how mistakes can lead to developmental defects and diseases such as cancer.
Michael Hothorn is piecing together how plants sense essential nutrients in the soil and send signals from cell to cell. A molecular understanding of how plants detect and respond to changes in phosphorus levels, for example, could help researchers engineer crops that can survive when nutrients are scarce.
Shalev Itzkovitz studies the design principles of mammalian tissues. He's taking a close-up look at individual cells to figure out how they work together in organs such as the intestine, liver, and pancreas. Advanced imaging techniques combined with single cell sequencing will help researchers determine the job description of cells in different organs.
Martin Jinek is investigating how protein and RNA molecules team up to control gene expression and protect the genome. He has pioneered work on the powerful genome-editing system known as CRISPR-Cas9, and revealed key details of this system at the atomic level. His work could spur the development of new, cutting-edge technologies for editing genomes and genetic therapies.
Luis Larrondo is unwinding the secrets of biological clocks, which help living organisms, including humans, plants and fungi, stay in sync with the Earth's daily rhythms. His research draws upon synthetic biology as well as optogenetics to probe the molecular components that keep biological clocks ticking.
Human genomic DNA is packaged with histone proteins into tightly-wound bundles of fiber called chromatin. Guohong Li has used an imaging technique called cryo-electron microscopy to visualize these twisted fibers in 3D at a detail previously unseen. Now, he wants to view the fibers at atomic resolution, and figure out the role of the histones wrapped inside.
A suite of chemical tags decorates the genomes of humans, plants, and other multicellular organisms. Ryan Lister is inventing new tools to edit these tags, a type of epigenetic modification, which can regulate gene expression, cell differentiation, and more. He also wants to explore their role in brain development, which could offer new insights into neurological disorders.
Mitochondria, which generate energy for cells and regulate programmed cell death, are vulnerable to damage. Ying Liu is using worm genetics and biochemistry to investigate the cellular pathways that sense mitochondrial dysfunction and activate stress responses. Defects in these pathways may contribute to metabolic disorders, neurodegenerative diseases and cancer.
Laura Mackay is working to identify pathways that guide the development of tissue-resident memory T cells, immune cells that reside in the body's peripheral tissues and protect against local infections. She wants to harness these cells to create new therapies for infectious disease, cancer, and autoimmune diseases.
Judit Makara is investigating how neurons in the brain's hippocampus support creation of memories. She is interested in the synaptic and dendritic processing mechanisms that promote the recruitment of individual neurons into ensembles with coordinated activity to store information about places or events.
Tomas Marques-Bonet is assessing genomic diversity among great apes. His work will help us understand the biological processes and features that make us human and has implications for conservation biology. He is also using comparative genomics to study changes in gene regulation and the genomic consequences of domestication.
Seth Masters uses personalized medicine to identify genetic changes that cause severe inflammatory diseases early in life. These studies teach us about how the innate immune system works, and may also provide targets for the development of drugs to treat more common inflammatory conditions such as heart disease, inflammatory bowel disease, type 2 diabetes and neurological disorders.
Ruben Moreno-Bote is interested in the idea that although the human brain can solve complex problems, it sometimes falls short on simple tasks. He is combining theoretical and experimental approaches to identify the factors that limit the amount of information stored in the brain.
As stem cells develop into specialized cells, their cell fates are influenced by the biochemical pathways that process nutrients to synthesize cellular materials and convert food to energy. Shyh-Chang Ng is studying how these metabolic processes regulate muscle regeneration during aging. His work could deepen our understanding of the effects of nutrition and exercise, and suggest strategies for treating the aging-induced metabolic syndrome.
Zaza Ndhlovu is investigating how the immune system is affected when patients with HIV begin combination antiretroviral therapy very early in the course of disease. His goal is to learn whether brief exposure to the virus is sufficient to prime a protective immune response that might one day be boosted by a vaccine.
Fredros Okumu is developing species-specific methods of eliminating the malaria-transmitting mosquito Anopheles funestus, with the goal of stopping the disease's transmission in two districts in southeastern Tanzania. Although A. funestus is not the most populous mosquito species in the region, it is responsible for 82-95 percent of local malaria infections.
Cellular perturbations, such as changes in nutrient or oxygen levels or accumulation of misfolded proteins, can be indicative of pathogen presence or disruption in normal physiology. Fabiola Osorio studies how the immune system recognizes and responds to signs of cellular stress for regulation of immunity.
Biophysicist Hye Yoon Park is developing imaging technologies to visualize the cellular and molecular processes the brain uses to form, consolidate, and retrieve memories. She will use the new techniques to study how neuronal activity alters gene expression to rewire neural circuits during learning.
Joseph Paton has discovered key signals in the brain involved in timing and decision-making. He is investigating the circuit mechanisms that generate these signals and transform them into actions. His work will help explain how animals free themselves from the immediacy of the current moment to learn and plan.
Nicolas Plachta is using single-cell imaging technologies devised in his lab to study how developing embryos take shape. He wants to understand the molecular mechanisms that govern changes in cell fate, shape, and position and how these changes are coordinated across an entire embryo.
Thomas Pucadyil is studying how biological membranes -- protective barriers that are highly resilient to rupture -- split apart to allow for the packaging and transport of cellular materials. He is searching for membrane fission catalysts that cells use to manage this energetically demanding process.
Hai Qi is exploring how the immune system generates and maintains memory cells that remember past infections and stay poised to produce antibodies against returning pathogens. His research may open new avenues for vaccine development and suggest better ways to control autoimmune diseases.
Asya Rolls wants to understand the connections between the brain and the immune system. She is particularly interested in how brain activity influences the immune system's ability to find and destroy tumors. Her research could reveal new ways to harness the body's inherent disease-fighting potential.
Marvin Tanenbaum is developing an imaging approach that will allow researchers to observe individual messenger RNA molecules as they are translated into proteins in living cells. He will use the method to investigate how translation is regulated to control the fate and function of cells.
Wai-Hong Tham is studying how malaria parasites interact with their human hosts. Specifically, she wants to understand how Plasmodium vivax, the dominant malaria parasite in countries outside of sub-Saharan Africa, recognizes and invades red blood cells inside the human body.
Yanli Wang is studying mechanisms of two bacterial anti-virus defense systems. She is using structural biology to learn how the CRISPR-Cas and Argonaute systems use small molecules of RNA or DNA to find and cleave foreign genetic material. She is also looking for ways to modify their RNA/DNA-cleaving components to increase their efficiency as genome editing tools.
Immediately after an egg is fertilized, DNA and its packaging proteins (histones) undergo drastic reorganization so that cells can acquire new identities in early embryos. However, how this is achieved remains poorly understood due to the extremely scarce experimental samples. By developing ultrasensitive tools for chromatin analysis, Wei Xie is working to decipher how such reprogramming occurs and whether chromatin associated "epigenetic" information can be passed on to the next generation.
Manuel Zimmer is using the roundworm Caenorhabditis elegans to study the dynamics of neural networks. Using a whole-brain imaging approach developed in his lab, he aims to uncover the fundamental computations and their underlying mechanisms neural circuits use to interpret sensory information and generate appropriate behaviors.
The Howard Hughes Medical Institute plays a powerful role in advancing scientific research and education. Its scientists, located across the country and around the world, have made important discoveries that advance both human health and our fundamental understanding of biology. The Institute also aims to transform science education into a creative, interdisciplinary endeavor that reflects the excitement of real research. HHMI is headquartered in Chevy Chase, Maryland. http://www.
Guided by the belief that every life has equal value, the Bill & Melinda Gates Foundation works to help all people lead healthy, productive lives. In developing countries, it focuses on improving people's health and giving them the chance to lift themselves out of hunger and extreme poverty. In the United States, it seeks to ensure that all people - especially those with the fewest resources - have access to the opportunities they need to succeed in school and life. Based in Seattle, Washington, the foundation is led by CEO Sue Desmond-Hellmann and Co-chair William H. Gates Sr., under the direction of Bill and Melinda Gates and Warren Buffett. http://www.
The Wellcome Trust is a global charitable foundation dedicated to improving health. We support bright minds in science, the humanities and the social sciences, as well as education, public engagement and the application of research to medicine. Our investment portfolio gives us the independence to support such transformative work as the sequencing and understanding of the human genome, research that established front-line drugs for malaria, and Wellcome Collection, our free venue for the incurably curious that explores medicine, life and art. http://www.
The Calouste Gulbenkian Foundation is an international foundation that bears the name of businessman, art collector and philanthropist of Armenian origin, Calouste Sarkis Gulbenkian (1869-1955). For almost 60 years, the Foundation has been carrying out extensive activities both in Portugal and abroad through the development of in-house projects -- or in partnership with other institutions -- and by awarding scholarships and grants. Headquartered in Lisbon, where Calouste Gulbenkian spent his last years, the Foundation is also home to a scientific investigation centre in Oeiras, and runs delegations in Paris and London -- cities where Calouste Gulbenkian lived. http://www.

Lung cancer tumors were prevented in mice by a novel small molecule that directly activates a tumor suppressor protein.
Goutham Narla, MD, PhD, Pardee-Gerstacker Professor in Cancer Research, Associate Professor at Case Western Reserve University School of Medicine and member of the Case Comprehensive Cancer Center in Cleveland, Ohio.
Cells are constantly turning proteins on and off via molecular switches--phosphate molecules--that have become common drug targets. Said Dr. Narla, "All the drugs we currently have to treat our cancer patients target what we call kinases, which attach phosphate molecules to proteins. But equally important to this are the enzymes that take the phosphate off."
One enzyme--PP2A--can "turn off" tumor proteins by removing phosphate molecules attached to them. But according to Dr. Narla, "This tumor suppressor is turned off in pretty much every major cancer. Its inactivation is essential for a normal cell to become a cancer cell."
Narla and his team decided to take an unconventional approach to cancer drug development by seeking molecules that directly target PP2A, in an effort to reactivate its tumor suppressor properties.
Forty-five researchers, including eight students from the Young Scientist Foundation and Mark R. Chance, PhD, Vice Dean for Research at Case Western Reserve School of Medicine, collaborated to screen a series of drug-like molecules for their ability to reactivate PP2A in lung cancer cells and prevent lung cancer tumors in mice. The prototype drug molecules were created from FDA-approved medications by Michael Ohlmeyer, PhD, Associate Professor at Icahn School of Medicine at Mount Sinai.
The team found one particular prototype drug can attach to a subunit of the PP2A protein, effectively activating the enzyme. As Narla explained, the study is the first to use a small molecule to directly activate an enzyme that removes phosphate molecules. "There are indirect ways that have been shown to get at these kinds of enzymes, but this is the first example of a direct activation of one. Our drug actually binds to and turns on PP2A."
The prototype drug also prevented lung cancer cells from proliferating in laboratory models, including mouse models. Mice injected with the drug had fewer lung cancer tumors and did not experience weight loss or behavioral abnormalities associated with other cancer medications. In the mouse models, the drug was comparably effective to currently available combination therapies used to slow lung cancer progression.
To confirm exactly where the drug attaches to PP2A, the researchers also developed lung cancer cells with specific mutations at the putative drug binding site. Mice with tumors created from the mutated cancer cells did not benefit from the prototype drug, as the drug could not attach to and reactivate PP2A. The results confirmed that the prototype drug attaches to PP2A at two specific amino acids within a subunit of the enzyme, information that could help inform other drug developers.
"This is the first example ever of a cancer drug that directly binds to and activates an enzyme that removes phosphate molecules. Therefore our findings could have broad applicability to the treatment of a large number of human cancers, including lung cancer as we demonstrated in this paper," Narla said.
"There are some 2,000 plus papers on the role of PP2A in cancer. Breast cancer, prostate cancer, lung cancer, brain cancer, childhood cancers, ovarian cancer, endometrial cancer, every major cancer involves the inactivation of this protein," Narla noted. "Molecules that allow us to turn it back on, like the one in our study, have the potential to work in a broad range of cancer patients."
"We are continuing to test our drug in a large series of animal models. If things continue to go well, we hope to start clinical trials next year with this drug. Our initial clinical trials would be quite broad, and would include a number of diverse cancer patients, including patients with lung cancer." Narla said.
"The Young Scientists supported by the Young Scientist Foundation, http://www. , were integral to these discoveries," Narla added. "I think their contributions highlight, in an increasingly competitive funding environment, the importance of STEM and the benefit of engaging youth early on in biomedical research."
The study included pre-clinical cell and animal models that may not necessarily translate to human lung cancer. Mice were implanted with lung cancer tumors, rather than developing them on their own, and treated with the drug for only four weeks. Long-term effects of the prototype drug remain unknown.
The study was funded by the National Institutes of Health (NIH), Howard Hughes Medical Institute (HHMI), Case Western Reserve University (CWRU), University Hospitals through the Harrington Discovery Institute, and Dual Therapeutics. The Icahn School of Medicine at Mount Sinai on behalf of the authors GN, MO, NSD, DBK have filed patents covering composition of matter on the small molecules used in the study for the treatment of human cancer and other diseases. Dual Therapeutics LLC has licensed this intellectual property for the clinical and commercial development of this series of small molecule PP2A activators. The authors GN, MO, YI, NSD, DBK have an ownership interest in Dual Therapeutics LLC. GN and MO are consultants for Dual Therapeutics LLC.
For more information about Case Western Reserve University School of Medicine, please visit: http://case. .

-- An international team of researchers from the University of California, Los Angeles (UCLA, USA) and the Braunschweig University of Technology (Germany) has developed an approach to enhance the sensitivity of smartphone based fluorescence microscopes by ten-fold compared to previously reported mobile phone based handheld microscopes. This is an important development toward the use of mobile phones for advanced microscopic investigation of samples, sensing of disease biomarkers, tracking of chronic conditions, and molecular diagnostics and testing in general.Fluorescence is one of the predominant detection modalities for molecular diagnostic tools and medical tests due to the sensitivity and specificity that it enables. An important need in smartphone-based microscopy and sensing techniques is to improve the detection sensitivity to enable quantification of extremely low concentrations of target molecules, for example cancer biomarkers, pathogen proteins or even DNA. Therefore, these recent results on enhanced fluorescence microscopy using mobile phones are especially important to provide highly sensitive, mobile and cost-effective readers for molecular diagnostic tests, potentially impacting global health and point of care applications.The sensitivity enhancement was accomplished by using a thin silver film on which the fluorescent samples were placed. Although the thickness of the silver film is approximately two thousand fold thinner than the human hair, it is sufficient to enhance the strength of the excitation light, especially in the vicinity of the fluorescent samples. This is achieved by coupling the energy of an optical beam into plasmonic waves (known as surface plasmon polaritons) that are formed by electron oscillations in the silver film. This plasmonics based optical enhancement resulted in a cost-effective mobile phone fluorescence microscope that weighs approximately 370 grams including the smartphone, and achieved repeatable detection of single quantum-dots and as few as ~50-80 fluorophores per sample spot. Compared to standard benchtop fluorescence microscopes, this mobile device is more than twenty fold cheaper and lighter."We are now capable of detecting a few tens of fluorophores for each sample spot using a low-cost pocket microscope, enabled by plasmonics and mobile phones. This will create numerous new opportunities for bringing advanced molecular testing and diagnostics for tackling global health problems, especially in developing countries," said Aydogan Ozcan, who led the research team at UCLA and is a Chancellor's Professor of Electrical Engineering and Bioengineering and an associate director of the California NanoSystems Institute (CNSI).The first author of the research is Dr. Qingshan Wei, a former postdoctoral scholar at Ozcan Lab, who has recently moved to North Carolina State University (USA) as an Assistant Professor at the Department of Chemical and Biomolecular Engineering.This collaboration between UCLA (Ozcan Lab) and Braunschweig University of Technology (Tinnefeld Lab) was published in Scientific Reports. Earlier this year, Ozcan Lab also reported targeted DNA sequencing and mutation analysis using a mobile phone based multimodal microscope, which was published in Nature Communications.Ozcan Lab was supported by the National Science Foundation, Office of Naval Research, Army Research Office, National Institutes of Health, Vodafone Americas Foundation and Howard Hughes Medical Institute (HHMI).Scientific Reports publication:Qingshan Wei, Guillermo Acuna, Seungkyeum Kim, Carolin Vietz, Derek Tseng, Jongjae Chae, Daniel Shir, Wei Luo, Philip Tinnefeld and Aydogan Ozcan, "Plasmonics Enhanced Smartphone Fluorescence Microscope,"Scientific Reports 7, Article number: 2124 (2017), doi:10.1038/s41598-017-02395-Ozcan Lab: http://innovate.ee.ucla.edu/

Many things go wrong in cells during the development of cancer. At the heart of the chaos are often genetic switches that control the production of new cells. In a particularly aggressive form of leukemia, called acute myeloid leukemia, a genetic switch that regulates the maturation of blood stem cells into red and white blood cells goes awry. Normally, this switch leads to appropriate numbers of white and red blood cells. But patients with acute myeloid leukemia end up with a dangerous accumulation of blood stem cells and a lack of red and white blood cells -- cells that are needed to supply the body with oxygen and fight infections.
Now, researchers at Caltech and the Sylvester Comprehensive Cancer Center at the University of Miami are narrowing in on a protein that helps control this genetic switch. In healthy individuals, the protein, called DPF2, stops the production of red and white blood cells when they do not need to be replaced. That is, it turns the switch off. But the protein can be overproduced in acute myeloid leukemia patients. The protein basically sits on the switch, preventing it from turning back on to make the blood cells as needed. Patients who overproduce DPF2 have a particularly poor prognosis.
In a new study, to be published the week of May 22, 2017, in the journal Proceedings of the National Academy of Sciences, the researchers demonstrate new ways to impede DPF2, potentially rendering acute myeloid leukemia more treatable. They report new structural and functional details about a fragment of DPF2. This new information reveals targets for the development of drugs that would block the protein's function.
"Many human diseases, including cancers, arise because of malfunctioning genetic switches," says André Hoelz, the corresponding author of the study. Hoelz is a professor of chemistry at Caltech, a Heritage Medical Research Institute (HMRI) Investigator, and a Howard Hughes Medical Institute (HHMI) Faculty Scholar. "Elucidating how they work at atomic detail allows us to begin the process of custom tailoring drugs to inactivate them and in many cases that is a significant step towards a cure."
Red and white blood cells are constantly regenerated from blood stem cells, which reside in our bone marrow. Like other stem cells, blood stem cells can live forever. It is only when they become differentiated into specific cell types, such as red and white blood cells, that they then become mortal, or acquire the ability to die after a certain period of time.
"Our bodies use a complex series of genetic switches to differentiate a blood stem cell into many different cell types. These differentiated cells then circulate in the blood and serve a variety of different functions. When these cells reach the end of their lifespan they need to be replaced," says Hoelz. "This is somewhat like replacing used tires on a car."
To investigate the role of DPF2 and learn more about how it controls the genetic switch for making blood cells, the Hoelz group partnered with Stephen D. Nimer, co-corresponding author of the paper and director of the Sylvester Comprehensive Cancer Center, and his team. First, Ferdinand Huber and Andrew Davenport -- both graduate students at Caltech in the Hoelz group and co-first-authors of the new study--obtained crystals of a portion of the DPF2 protein containing a domain known as a PHD finger, which stands for planet homeodomain. They then used X-ray crystallography, a process that involves exposing protein crystals to high-energy X-rays, to solve the structure of the PHD finger domain. The technique was performed at the Stanford Synchrotron Radiation Lightsource, using a dedicated beamline of Caltech's Molecular Observatory.
The results revealed how DPF2 binds to a DNA-protein complex, called the nucleosome, to block the production of red and white blood cells. The protein "reads" various signals displayed on the nucleosome surface by adopting a shape that fits various modifications on the nucleosome complex, like the different shaped pieces of a jigsaw puzzle. Once the protein binds to this DNA locus, DPF2 turns off the switch that regulates blood cell differentiation.
The next step was to see if DPF2 could be blocked in human blood stem cells in the lab. Sarah Greenblatt, a postdoctoral associate in Nimer's group and co-first author of the study, used the structural information from Hoelz's group to create a mutated version of the protein. The Nimer group then introduced the mutated protein in blood stem cells, and found that the mutated DPF2 could no longer bind to the nucleosome. In other words, DPF2 could no longer inactivate the switch for making blood cells.
"The mutated DPF2 was unable to bind to specific regions in the genome and could not halt blood stem cell differentiation," says Huber. "Whether DPF2 can also be blocked in the cancer patients themselves remains to be seen." The researchers say a structural socket in DPF2, one of the puzzle-piece-like regions identified in the new study, is a good target for candidate drugs.
The study, titled "Histone-Binding of DPF2 Mediates Its Repressive Role in Myeloid Differentiation," was funded by a PhD fellowship of the Boehringer Ingelheim Fonds, a National Institutes of Health Research Service Award, the National Cancer Institute of the National Institutes of Health, a Faculty Scholar Award of the Howard Hughes Medical Research Institute, the Heritage Medical Research Institute, Caltech startup funds, the Albert Wyrick V Scholar Award of the V Foundation for Cancer Research, a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research, and a Teacher-Scholar Award of the Camille & Henry Dreyfus Foundation. Other authors are Concepcion Martinez and Ye Xu of the University of Miami and Ly P. Vu of the Memorial Sloan Kettering Cancer Center.

A crystal structure of a portion of human DPF2, a protein that controls a genetic switch that tells blood stem cells when to become red and white blood cells. Orange and yellow regions illustrate the DPF2 'reader' domain, which is stabilized by zinc ions, represented as red and grey spheres. Credit: Hoelz Lab/Caltech Many things go wrong in cells during the development of cancer. At the heart of the chaos are often genetic switches that control the production of new cells. In a particularly aggressive form of leukemia, called acute myeloid leukemia, a genetic switch that regulates the maturation of blood stem cells into red and white blood cells goes awry. Normally, this switch leads to appropriate numbers of white and red blood cells. But patients with acute myeloid leukemia end up with a dangerous accumulation of blood stem cells and a lack of red and white blood cells—cells that are needed to supply the body with oxygen and fight infections.
Now, researchers at Caltech and the Sylvester Comprehensive Cancer Center at the University of Miami are narrowing in on a protein that helps control this genetic switch. In healthy individuals, the protein, called DPF2, stops the production of red and white blood cells when they do not need to be replaced. That is, it turns the switch off. But the protein can be overproduced in acute myeloid leukemia patients. The protein basically sits on the switch, preventing it from turning back on to make the blood cells as needed. Patients who overproduce DPF2 have a particularly poor prognosis.
In a new study, to be published the week of May 22, 2017, in the journal Proceedings of the National Academy of Sciences, the researchers demonstrate new ways to impede DPF2, potentially rendering acute myeloid leukemia more treatable. They report new structural and functional details about a fragment of DPF2. This new information reveals targets for the development of drugs that would block the protein's function.
"Many human diseases, including cancers, arise because of malfunctioning genetic switches," says André Hoelz, the corresponding author of the study. Hoelz is a professor of chemistry at Caltech, a Heritage Medical Research Institute (HMRI) Investigator, and a Howard Hughes Medical Institute (HHMI) Faculty Scholar. "Elucidating how they work at atomic detail allows us to begin the process of custom tailoring drugs to inactivate them and in many cases that is a significant step towards a cure."
Red and white blood cells are constantly regenerated from blood stem cells, which reside in our bone marrow. Like other stem cells, blood stem cells can live forever. It is only when they become differentiated into specific cell types, such as red and white blood cells, that they then become mortal, or acquire the ability to die after a certain period of time.
"Our bodies use a complex series of genetic switches to differentiate a blood stem cell into many different cell types. These differentiated cells then circulate in the blood and serve a variety of different functions. When these cells reach the end of their lifespan they need to be replaced," says Hoelz. "This is somewhat like replacing used tires on a car."
To investigate the role of DPF2 and learn more about how it controls the genetic switch for making blood cells, the Hoelz group partnered with Stephen D. Nimer, co-corresponding author of the paper and director of the Sylvester Comprehensive Cancer Center, and his team. First, Ferdinand Huber and Andrew Davenport—both graduate students at Caltech in the Hoelz group and co-first-authors of the new study—obtained crystals of a portion of the DPF2 protein containing a domain known as a PHD finger, which stands for planet homeodomain. They then used X-ray crystallography, a process that involves exposing protein crystals to high-energy X-rays, to solve the structure of the PHD finger domain. The technique was performed at the Stanford Synchrotron Radiation Lightsource, using a dedicated beamline of Caltech's Molecular Observatory.
The results revealed how DPF2 binds to a DNA-protein complex, called the nucleosome, to block the production of red and white blood cells. The protein "reads" various signals displayed on the nucleosome surface by adopting a shape that fits various modifications on the nucleosome complex, like the different shaped pieces of a jigsaw puzzle. Once the protein binds to this DNA locus, DPF2 turns off the switch that regulates blood cell differentiation.
The next step was to see if DPF2 could be blocked in human blood stem cells in the lab. Sarah Greenblatt, a postdoctoral associate in Nimer's group and co-first author of the study, used the structural information from Hoelz's group to create a mutated version of the protein. The Nimer group then introduced the mutated protein in blood stem cells, and found that the mutated DPF2 could no longer bind to the nucleosome. In other words, DPF2 could no longer inactivate the switch for making blood cells.
"The mutated DPF2 was unable to bind to specific regions in the genome and could not halt blood stem cell differentiation," says Huber. "Whether DPF2 can also be blocked in the cancer patients themselves remains to be seen." The researchers say a structural socket in DPF2, one of the puzzle-piece-like regions identified in the new study, is a good target for candidate drugs.
Explore further: Researchers show p300 protein may suppress leukemia in MDS patients
More information: Ferdinand M. Huber el al., "Histone-binding of DPF2 mediates its repressive role in myeloid differentiation," PNAS (2017). www.pnas.org/cgi/doi/10.1073/pnas.1700328114

In a paper published today in Nature, the team lays out its methodology for using Betzig's lattice light sheet microscope in combination with image-tracking technology developed in Drexel's Computational Image Sequence Analysis Lab, led by Andrew Cohen, PhD, to produce 3-D time lapse videos of organelle movement and generate quantitative data on their interactions.
"The cell biology community has recognized for many years that the cytoplasm is full of many different types of organelles, and the field is recognizing more and more how significant cross-talk between these organelles is in the form of close contacts between these organelles," said Jennifer Lippincott-Schwartz, PhD, of HHMI's Janelia Research Campus, and senior author of the study. "When two organelles come close to each other they can transfer small molecules like lipids and calcium and communicate with each other through that transfer. But no one has been able to look at the whole set of these interactions at any particular time. This technology is providing a way to do that. But this paper is about a whole new technology, being able to tag six different objects with six different fluorophores, and unmixing the fluorophores so that you can observe the six different objects discretely."
Betzig's microscopy technique uses layers of light grids that interact with fluorescent protein-tagged cells to build a 3D microscopic image. At Janelia Research Campus, Betzig and Lippincott-Schwartz have refined that technology to produce a detailed look inside the cell by tagging each organelle type with its own color.
"The challenge is analyzing this data," Lippincott-Schwartz said. "It requires being able to simultaneously track these six different objects in 3D. What Andy Cohen and his group have done with the software system they have developed is enable us to really look at this in more quantitative ways than would be possible with conventional tools."
Cohen's lab developed a tool called LEVER 3-D in 2015 to help researchers study 3-D images of neural stem cells. It applies an advanced image segmentation algorithm they developed that can identify boundaries of cells and track their movements. Prior to this technology being available to microbiologists, the processing of microscopic images and time-lapse footage would take massive amounts of time because they would have to create lineage trees by hand and attempt to follow cell changes by making their own observations when comparing images.
This process is even more involved when multiple objects are being tracked in three dimensions. Lippincott-Schwartz's group used a battery of computer programs to filter out all the different pieces of light spectra emitted by the organelles, to begin to bring the 3-D images and video into focus. The process, called "linear unmixing," required more than 32 cores of a computer work station to sift through 7 billion sets of six-color images, pixel by pixel.
Typically they would use expensive commercial software programs to stitch them into a 3-D volume to go about studying them. But these programs are expensive and time-consuming to use, and were not capable of the sophisticated analysis for tracking moving objects in order to make quantitative measurements of their behaviors and particularly how they interact.
Cohen's algorithm automates the entire process, which saves researchers a lot of time and it also lets them ask – and answer – more questions about what the cells are doing. He further verified the data by working with Drexel colleague Uri Herschberg, PhD, an associate professor in the School of Biomedical Engineering, Science and Health Systems and College of Medicine, to check it against 2-D images of the cells.
"It's some really impressive footage that gives biologists this ability to look deeper and deeper into live cells and see things they've never seen before—like six different organelles in a living cell in true 3-D," said Cohen, a professor in Drexel's College of Engineering. "But it's also a lot of work to begin quantifying what they're seeing—and that's where we can help, by using our program to automate big portions of that process and glean valuable data from it."
Using the new technology to simultaneously look at six sets of organelles, Lippincott-Schwartz's teams at Janelia and at the National Institutes of Health are making exciting new observations. They are looking at how the organelles distribute themselves inside the cell, how often they interact with each other and where, when and how fast they move during various times in the cell's lifecycle.
"One very interesting outcome is that we found the largest organelle in the cell, which is the ER [endoplasmic reticulum], at any particular time point will be occupying about 25 percent of the volume of the cytoplasm, excluding the nucleus. But if you track the way it disperses through the cytoplasm over a short period of time, like 15 minutes, you see that it explores 95 percent of the whole cytoplasm during that time period," Lippincott-Schwartz said. "We can do this for all of the other organelles at the same time to see how the cytoplasm is being sensed through the dynamic motions of dispersive activities of these organelles."
Observing sub-cellular behavior is just the first application of this technology. Now that it has proven to generate usable data, the team will forge ahead to study what happens inside a cell when it is exposed to drug treatments and other common stresses on the system. The researchers suggest that it could be used to study many more than six types of microscopic objects. And it could help dig even deeper into the building blocks of life—into interactions of RNA particles and other proteins that play a role in a cell's function and the behavior of diseased cells.
"As these tools continue to improve they will give researchers both a better look at cell behavior and many options for gathering and analyzing that data," Cohen said. "They will be able to ask and answer increasingly complicated questions and that's going to lead to some very exciting and important discoveries."
Explore further: How plant cell compartments change with cell growth
More information: Alex M. Valm et al. Applying systems-level spectral imaging and analysis to reveal the organelle interactome, Nature (2017). DOI: 10.1038/nature22369

Life scientists keen to share their findings online before peer review are spoilt for choice. Whereas physicists gravitate to one repository — the ‘preprint’ server arXiv — life sciences has a fast-growing roster of venues for preprints. There’s the biology-focused bioRxiv, and a biology section on arXiv too. But other sites have sprouted up in the past year, or soon will do, and these too provide opportunities for life sciences: ChemRxiv for chemistry, psyArXiv for psychology; even AgriXiv for agricultural sciences and paleorXiv for palaeontology.
Now, a coalition of biomedical funders and scientists is throwing its weight behind a ‘one-stop shop’ for all life-sciences preprints — a move that its backers argue should clarify any confusion and make it easier to mine the preprint literature for insights. On 13 February, ASAPbio, a grassroots group of biologists that advocates for preprints, issued a funding call to build a central preprint site; the US National Institutes of Health (NIH), the Wellcome Trust and several other leading funders announced their support for the concept.
“The landscape could become fragmented very quickly,” says Robert Kiley, head of digital services at the London-based Wellcome Trust. “We want to find a way of ensuring that, although this content is distributed far and wide, there’s a central place that brings it all together”.
The details of the service are inchoate: its scope will depend on specific scientific fields and their funders, says Jessica Polka, the director of ASAPbio. But as well as aggregating content from other biology-focused preprint sites, ASAPbio wants the site to mesh with arXiv and with ChemRxiv, which the American Chemical Society in Washington DC plans to launch soon.
Proponents hope that a central site will lure biologists to embrace the practice as wholeheartedly as physical scientists have. Physics manuscripts routinely appear at arXiv.org months before publication in peer-reviewed journals, as researchers race to release their findings online before their rivals. And preprints are now accepted currency in determining priority for a discovery, as well as in winning grants and jobs. ArXiv handles more than 100,000 manuscripts each year in physics, mathematics and computer science. (The largest life-sciences preprint server, bioRxiv, posted around 5,000 manuscripts in 2016.)
“One of the lessons of arXiv is that users prefer ‘one-stop shopping’,” says Paul Ginsparg, a theoretical physicist at Cornell University in Ithaca, New York, who founded the site in 1991. He could see a preprint aggregation site for life sciences working just as well, so long as disparate sites can agree on uniform technical standards.
A central preprint service could also help scientists to use automated software to mine the literature for insights, says Ron Vale, a cell biologist at the University of California, San Francisco, and a founder of ASAPbio. At the moment, researchers who want to mine peer-reviewed papers face myriad hurdles, from publisher copyrights to disparate websites that make bulk-downloading difficult. “We’re trying to think of preprints as data,” says Vale. It would be both technically and legally straightforward for computers to crawl the collection of preprints on the central site, where they would appear under an open-access licence.
Polka would not say how much ASAPbio expects the site to cost, but arXiv funding totals about US$925,000 a year, paid for by a global collective of more than 200 research institutions and funders; a large donation has come from the Simons Foundation, a private organization based in New York City. Ginsparg says expenses for the life-sciences site should be around $5 a manuscript, once it is publishing tens of thousands of manuscripts each year. Funders who support the site have not yet committed to paying for it, but Kiley expects that funders will do so once details are hashed out.
Other funders that have come out in support of the central service include the UK Medical Research Council, the Howard Hughes Medical Institute (HHMI), the Canadian Institutes of Health Research and the European Research Council. “That’s going to send a strong message to the science community that this kind of communication is encouraged,” says Vale. Last month, the HHMI announced that it would consider preprints in deciding whether or not to renew the prestigious five-year grants it gives to investigators.
Jason Hoyt, chief executive of the journal PeerJ (which also operates a preprint service), says he supports a central preprint site and that his company might bid to help create it. But such a site will succeed only if it can induce a large proportion of life scientists to view preprints as the dominant currency for career progression, he says. “The challenge is to overturn the thinking in biology.”
ASAPbio and the funders supporting a central preprint service emphasize that it’s no replacement for peer-reviewed journals. They note that the vast majority (over 80% in some fields) of arXiv posts wind up in journals. “We really see this as a complement to the journal system, rather than anything that could be threatening,” says Polka, who adds that a central service will not attempt to organize peer review.
That would be a missed opportunity, says Rebecca Lawrence, managing director of London-based F1000Research, which posts papers before they are peer reviewed at the journal (but does not consider these preprints). She would like to see peer review occur through a central preprint service, thereby reducing the influence that traditional journals have on scientists’ careers. “It’s a great shift in the right direction,” Lawrence says, “but I think we need to go a lot further.”
Ginsparg ultimately envisions a "federated repository" that spans scientific disciplines and aggregates preprints from arXiv and other fields, including the life sciences. “Twenty-five years ago, I thought we’d be much closer to that point by now, but I still think it’s inevitable,” he says.

FILE - This Tuesday, April 26, 2016 file photo shows The Associated Press logo in New York. The Associated Press is teaming with the Howard Hughes Medical Institute’s Department of Science Education to expand its coverage of science, medicine and health journalism. (AP Photo/Hiro Komae)
NEW YORK (AP) -- The Associated Press is teaming up with the Howard Hughes Medical Institute's Department of Science Education to expand its coverage of science, medicine and health journalism.
The initial collaboration includes two pilot projects. With the first project, AP will create and distribute a series of stories, profiles, videos and graphics focusing on genetic medicine. The second project will look at a variety of science topics in the news that will help readers stay current on the latest science research and make informed decisions on topics ranging from the environment, to public health.
"This collaboration brings wider attention and new storytelling tools to evidence-based, factual science," AP Executive Editor Sally Buzbee said.
HHMI, based in Chevy Chase, Maryland, supports the advancement of biomedical research and science education. The organization's origin dates back to the late 1940s when a small group of physicians and scientists advised Hughes. The medical institute was created in 1953.
The primary purpose of the organization is to promote human knowledge in the field of the basic sciences and its effective application for the benefit of mankind, according to its charter. In fiscal 2016, it provided $663 million in U.S. biomedical research and $86 million in grants and other support for science education.
HHMI's Department of Science Education, the largest private, nonprofit supporter of science education in the country, will provide funding for the AP projects. The funding will allow AP to increase the amount of science-related stories it provides to news organizations and add more journalists to support its current science reporting team. HHMI will also offer expert background information and educational material.
While the AP will receive funding and utilize HHMI's expertise when crafting its content, it maintains full editorial control of published material.
"We're proud to stand shoulder to shoulder with the world's most respected news organization to ensure that the best evidence around important scientific topics is presented clearly and distributed widely," said Sean B. Carroll, vice president of HHMI's Department of Science Education.